The present invention relates to pharmaceutical compositions based on polyaromatic compounds of use in particular as antitumour medicaments.
In 1999, cytotoxic treatments (chemotherapy) used to reduce the size of cancerous tumours, to suppress the development of the tumour process or indeed even, in still too few cases, to eliminate clumps of cancer cells and the risk of metastases, combine chemical substances which have been recently introduced with to others which have been used for several decades. For example, 5-fluorouracil (5-FU), recognized for nearly 40 years as one of the most active treatments for colorectal cancer, can be replaced by one or other of the specific inhibitors of topoisomerase I (irinotecan or topotecan) when the tumour is no longer sensitive to 5-FU. More generally, the therapeutic arsenal available for treating colorectal tumours will also be enriched with the availability of oxaliplatin, novel in situ xe2x80x9cdonorsxe2x80x9d of 5-FU or selective inhibitors of thymidylate synthetase. This coexistence is not limited to the treatment of colorectal cancers since, in addition, the chemotherapy of breast, ovarian and lung cancers now makes wide use of the family of taxane derivatives (paclitaxel, docetaxel). The need for more effective and better tolerated treatments, thus improving the survival and the quality of life of the patients, is imperative since, still taking the example of colorectal tumours, it has been estimated (S. L. Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that, in the United States alone, over 131 000 new cases were diagnosed in 1997, 54 000 of which were responsible for the death of the patient. It is the awareness of this situation which has prompted the inventors to focus their attention on a family of polyaromatic compounds which have not yet been studied to any great extent, identified in the Ascidia of warm seas, in order to develop a novel medicinal chemistry intended to select synthetic compounds resulting from chemical design/modulation research which possess a significant cytotoxic activity at the therapeutic level.
The seas and oceans which cover more than 70% of the surface of the planet harbour marine plants and sponges, which living species, under gradual systematic pharmacognosic, have been shown to be able to contain complex alkaloids exhibiting advantageous pharmacological properties. For example, the sponges Cryptotheca crypta and Halichondria okadai have formed the subject of in-depth studies since the discovery of the presence, in their cells, of cytarabine or of halichondrin B. It is the same for the tunicates, since the isolation of aplidine from the tunicate Aplidium albicans, which lives in the Balearic Islands (Spain). Alkaloids with a tetrahydroisoquinolone structure have been isolated from the ascidian Ecteinascidia turbinata. Among these, ecteinascidin-743 has formed the subject of in-depth preclinical studies (E. Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130, p. 34) and of clinical trials intended to define its therapeutic potential as anticancer medicament (A. Bowman et al., NCI-EORTC symposium, 1998; Abst. 452, p. 118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst. 453, p. 118; M. J. X. Hillebrand et al., NCI-EORTC symposium; 1998; Abst. 455, p. 119; E. Citkovic et al., NCI-EORTC symposium, 1998; Abst. 456, p. 119). Novel pentacyclic acridine derivatives have also formed the subject of pharmacochemical studies (D. J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).
Other natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron Lett., 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug Design, 1995; 10: 333-46). Ascididemin has antiproliferative properties demonstrated on the model of murine leukaemia (P388 or L1210 lines) and described by F. J. Schmitz et al. (J. Org. Chem. 1991; 56: 804-8), B. Lindsay et al. (Bioorg. Med. Chem. Lett., 1995; 5: 739-42) and J. Kobayashi et al. (Tetrahedron Lett., 1988; 29: 1177-80), and on the model of human leukaemia as described by I. Bonnard et al. (Anti-cancer Drug Design, 1995; 10: 333-46). Mention may also be made of 2-bromoleptoclinidone, isolated from the ascidian Leptoclinides sp. by S. J. Bloor et al. (J. Am. Chem. Soc., 1987; 109: 6134-6) and synthesized by F. Bracher et al. (Heterocycles, 1989; 29: 2093-95) and then by M. E. Jung et al. (Heterocycles, 1994; 39; 2: 767-778). 2-Bromoleptoclinidone exhibits cytotoxicity with respect to the leukaemia cell model with an ED50 of 0.4 xcexcg/ml. The cytotoxic properties were confirmed by F. Bracher (Pharmazie, 1997; 52: 57-60), both in vitro, on sixty tumour cell lines in culture, and in vivo, on models of xenografts of human tumour cell lines (colon tumours SW-620 and HTC116, renal tumour A498 and melanoma LOX IM VI) implanted in mice.
Other compounds derived from ascididemin, such as 11-hydroxyascididemin, 11-methoxyascididemin, 11-phenylascididemin, 11-nitrophenylascididemin, 1-nitroascididemin, 3-nitroascididemin and neocalliactine, have been described chemically by various groups, such as those of F. J. Schmitz (J. Org. Chem., 1991; 56: 804-8) and Y. Kitahara et al. (Heterocycles, 1993; 36: 943-46; Tetrahedron Lett., 1997; 53, 17029-38), G. Gellerman et al. (Tetrahedron Lett., 1993; 34: 1827-30), S. Nakahara et al., (Heterocycles, 1993; 36: 1139-44) and I. Spector et al. (U.S. Pat. No. 5,432,172).
Meridine is another natural alkaloid extracted from the ascidian Amphicarpa meridiana or from the marine sponge Corticum sp. Meridine was isolated by F. J. Schmitz et al. (J. Org. Chem., 1991; 56: 804-808) and then described for its antiproliferative properties on a model of murine leukaemia (P388) and its antifungal properties in U.S. Pat. No. 5,182,287 (Gunawardana et al. of 23 Jan. 1993). Its cytotoxic properties on two human cell lines, colon cancer cells (HT-29) and lung carcinoma cells (A549), were reported by R. E. Longley et al. (J. of Nat. Products, 1993; 56: 915-920).
Mention may also be made, among these compounds, of cystodamine, a pentacyclic alkaloid isolated from the ascidian Cystodytes dellechiajei by N. Bontemps et al. (Tetrahedron Lett., 1994; 35: 7023-7026), which exhibits cytotoxic activity with respect to human leukaemia lymphoblasts.
A subject-matter of the present invention is compounds of general formula I and Ia 
in which:
R1, R2, R3, R4 and R5 are selected from hydrogen, halogens, C1-C6 alkyl groups, hydroxyl, xe2x80x94CHO, xe2x80x94OR8, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94CONHR8, xe2x80x94CONR8R9, xe2x80x94NH2, xe2x80x94NHR8, xe2x80x94N(R8)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94Cl, xe2x80x94NHCOR8, morpholino, nitro, SO3H, 
R8 and R9 being selected from C1-C6 alkyl groups and phenyl(C1-C4)alkyl groups and Ar being a C6-C14 aryl group,
R6 is selected from hydrogen, halogens, C1-C6 alkyl or xe2x80x94(CH2)nR10 groups with R10 being selected from halogens or xe2x80x94OH, (C1-C6)alkoxy or xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6)alkyl groups and n between 1 and 6, xe2x80x94CN, xe2x80x94CO2Et or xe2x80x94COR11 groups with R11 being selected from C1-C6 and phenyl(C1-C4)alkyl groups, and xe2x80x94NR12R13 groups with R12 and R13 selected, independently of one another, from hydrogen or C1-C6 alkyl, phenyl(C1-C4)alkyl or xe2x80x94(CH2)nR14 groups with R14 being selected from halogens or (C1-C6)alkoxy and xe2x80x94N(CH3)2 groups and n between 1 and 6,
Rxe2x80x94R7 is selected from hydrogen, groups of type (C1-C6)alkyl, phenyl(C1-C4)alkyl, xe2x80x94NR15R16 with R15 and R16 selected, independently of one another, from hydrogen, groups of type C1-C6 alkyl and phenyl(C1-C4)alkyl and xe2x80x94(CH2)nR17, with R17 selected from hydrogen, halogens or xe2x80x94OH or (C1-C6)alkoxy groups and n between 1 and 6,
and the addition salts of these compounds with pharmaceutically acceptable acids.
A specific group of compounds of the formula I and/or Ia is those in which:
R1, R2, R3, R4 and R5 are selected from hydrogen, halogens, C1-C6 alkyl groups, hydroxyl, xe2x80x94CHO, xe2x80x94OR8, xe2x80x94COOH, xe2x80x94CN, xe2x80x94CO2R8, xe2x80x94CONHR8, xe2x80x94CONR8R9, xe2x80x94NH2, xe2x80x94NHR8, xe2x80x94N(R8)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)2, xe2x80x94NHCOR8, morpholino, nitro, SO3H, 
R8 and R9 being selected from C1-C6alkyl groups and Ar being a C6-C14 aryl group.
The subject-matter of the present invention is more particularly the compounds selected from the compounds of formula (I) and of formula (Ia) in which R1, R2, R3, R4 and R5 are selected from hydrogen, halogens, C1-C6 alkyl groups, hydroxyl, xe2x80x94OR8, NO2, xe2x80x94NH2, xe2x80x94NHR8, xe2x80x94NH(R8)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94Cl, xe2x80x94NHCOR8, R8 being selected from C1-C6 alkyl groups,
R6 is selected from hydrogen, xe2x80x94(CH2)nR10 groups, with R10 being selected from halogens, the xe2x80x94Oxe2x80x94COxe2x80x94CH3 group, C1-C6 alkyl groups and N(R12R13) groups with R12 and R13 selected, independently of one another, from hydrogen or C1-C6 alkyl, benzyl or xe2x80x94(CH2)nR14 groups, with R14 being selected from halogens or (C1-C6)alkoxy and xe2x80x94N(CH3)2 groups and n between 1 and 6,
R7 selected from hydrogen or groups of type (C1-C6)alkyl, benzyl, xe2x80x94N(R15R16) with R15 and R16 selected from hydrogen, groups of type C1-C6 alkyl and benzyl, and xe2x80x94(CH2)nR17, with R17 selected from hydrogen, halogens or xe2x80x94OH or (C1-C6)alkoxy groups and n between 1 and 6,
and the addition salts of these compounds with pharmaceutically acceptable acids.
A group of preferred compounds is that composed of the compounds of formula I and Ia in which at least one of the R1, R2, R3, R4 and R5 groups is an OR8 group.
The xe2x80x9caddition salts with pharmaceutically acceptable acidsxe2x80x9d denote the salts which give the biological properties of the free bases without having an undesirable action. These salts can in particular be those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; metal acid salts, such as disodium orthophosphate and monopotassium sulphate, and organic acids.
Generally, the compounds of formula (I) and (Ia) can be obtained by a process which consists in:
a) reacting, according to a hetero Diels-Alder reaction, a quinolinedione of formula: 
xe2x80x83and an azadiene of formula: 
where X=CH3,
in order to obtain a mixture of compounds 
b) in optionally separating the compounds of formulae II and IIa,
c1) subsequently reacting a compound of formulae II and/or IIa with dimethylformamide dimethyl acetal, in order to obtain an enamine of formula: 
then functionalizing the enamines, in order to introduce the R6 and/or R7 substituents, and cyclizing, in order to obtain the compounds of formulae I and/or Ia,
or
c2) functionalizing and cyclizing at the same time, in order to obtain the compounds of formulae I and/or Ia,
d) optionally separating the compounds of formulae I and Ia.
In an alternative form, the compounds of formulae I or Ia in which R6 and R7 are hydrogens can be obtained by a process which consists in:
a) reacting: 
xe2x80x83and an azadiene of formula 
where X=CH2xe2x80x94CH2xe2x80x94NHBoc,
in order to obtain a mixture of compounds 
b) optionally separating the compounds of formulae II and IIa,
c) cyclizing a compound of formulae II and/or IIa, in order to obtain a compound of formulae I and/or Ia,
d) optionally separating the compounds of formulae I or Ia.
The reaction for cyclization of the compounds of formulae III and IIIa can be obtained under hot conditions in the presence of NH4Cl in an appropriate solvent.
When X=CH2xe2x80x94CH2xe2x80x94NHBoc, the compounds of formulae I and Ia are obtained directly in the presence of NaHCO3 in trifluoroacetic acid medium from the compounds of formulae II and IIa.
The functionalization for the introduction of the R6 substituent can be obtained with derived reactants, such as Rxe2x80x94COCl, ClCN, ClCO2Et, ClCH2OR, FClO3 or CH2=N+ (CH3)2Ixe2x88x92 (in CH3COOH).
The functionalization for the introduction of an R7 substituent can be obtained by a Mannich reaction with an aldehyde of formula R7xe2x80x94CHO.
In this case, the simultaneous cyclization can be obtained in the presence of excess ammonium chloride in acetic acid.
An example of substituted azadiene can be prepared according to the following scheme: 
The following examples illustrate the preparation of the compounds of formulae (I) and (Ia).
A-1xe2x80x94Synthesis of N-BOC-1-amino-2-hydroxypropane is (Compound 1)
4.2 g (29.7 mmol) of di-tert-butyl dicarbonate are added at 0xc2x0 C. to a solution of 2 ml (27 mmol) of 3-amino-1-propanol in a mixture of 60 ml of dioxane, 30 ml of water and 30 ml of 1N NaOH. The reaction mixture is kept stirred at ambient temperature overnight and then it is acidified to pH 1 using concentrated HCl. After several extractions (3 times 50 ml) with ethyl acetate (AcOEt), the organic phases are dried over MgSO4 and then concentrated on a rotary evaporator to give 4 g of the expected product in the form of a yellow oil.
Yield: 85%.
1H NMR (CDCl3): 1.25 (s, 9H); 2.50 (m, 2H); 3.05 (m, 2H); 3.45 (m, 2H); 5.40 (broad s, 1H).
A-2xe2x80x94Synthesis of N-BOC-3-aminopropanal (Compound 2)
18 g (103 mmol) of Compound 1, 1.62 g (10.4 mmol) of TEMPO (tetramethyl-1-piperidinyloxy, free radical), 2.9 g (10.45 mmol) of tetrabutylammonium chloride and 21 g (75.5 mmol) of N-chlorosuccinimide are suspended in 351 ml of NaHCO3/K2CO3 (0.5N/0.05N) and 351 ml of CHCl3. The reaction mixture is vigorously stirred for 2 hours. The organic phase is separated by settling, dried over MgSO4 and then concentrated on a rotary evaporator to give the expected aldehyde in the form of a light orange oil.
Yield: 100%
1H NMR (CDCl3): 1.35 (s, 9H); 2.44 (d, 2H, J=6.8 Hz); 3.21 (m, 2H); 4.90 (broad s, 1H); 6.04 (dd, 1H, J=8 and 15.6 Hz); 6.74 (td, 1H, J=6.8 and 15.6 Hz); 9.39 (d, 1H, J=8 Hz).
A-3xe2x80x94Synthesis of N-BOC-5-amino-2-penten-1-al (Compound 3)
11 g (66.7 mmol) of Compound 2 and 24.3 g (80 mmol) of formylmethylenetriphenylphosphorane (FMTP) are dissolved in 350 ml of benzene and then the reaction mixture is brought to reflux for 9 hours. After evaporating the solvent on a rotary evaporator, the residue is filtered a first time through silica [(1/1 CHCl3/heptane) then CHCl3] to remove the triphenyl-phosphine. A second filtration through silica (8/2 AcOEt/heptane) makes it possible to obtain 3.88 g of Compound 3 in the form of an orange-yellow oil.
Yield: 29%.
1H NMR (CDCl3): 1.47 (s, 9H); 2.60 (m, 2H); 3.38 (m, 2H); 4.82 (broad s, 1H); 6.18 (dd, 1H); 6.88 (td, 1H); 9.55 (d, 1H).
A-4xe2x80x94Synthesis of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (Compound 4)
3.88 g (19.5 mmol) of Compound 3 are added at 0xc2x0 C. to 1.47 ml (19.5 mmol) of dimethylhydrazine and 8 drops of acetic acid in 30 ml of ether. The reaction mixture is left stirring for 10 min and the organic phase is separated by settling and washed with 1N HCl and then with a saturated NaCl solution. After drying over MgSO4 and evaporating the solvent on a rotary evaporator, 4.4 g of hydrazone (Compound 4) are obtained in the form of an orange-yellow oil.
Yield: 94%.
1H NMR (CDCl3): 2.30 (s, 9H); 2.3 (m, 2H); 2.82 (m, 2H); 4.52 (broad s, 1H); 5.70 (td, 1H, J=6.8 and 15.6 Hz); 6.22 (ddd, 1H, J=0.8 and 8.8 and 15.6 Hz); 6.96 (d, 1H, J=8.8 Hz).
13C NMR (CDCl3): 28.15; 33.05; 39.58; 42.51; 78.77; 130.84; 130.95; 135;54; 155.68.
B-1: Synthesis of 4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-1b) and of 4-methylpyrido-[3,2-g]quinoline-5,10-dione (Intermediate II-1b)
A mixture of 0.5 g (3.14 mmol) of quinoline-5,8-dione, 0.35 g (3.14 mmol) of crotonaldehyde dimethylhydrazone and 0.45 ml (4.76 mmol) of acetic anhydride in 20 ml of CHCl3 are treated in an ultrasonic bath for 1 hour. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (CHCl3) to give 0.428 g of a mixture of the two isomers I-1a and II-1a in the form of a purple powder. This powder and 1.6 g (18.4 mmol) of MnO2 are suspended in 20 ml of CHCl3 and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH2Cl2/MeOH) to give:
Intermediate (I-1b): 4-methylpyrido[2,3-g]quinoline-5,10-dione
40 mg (Yield: 6%) in the form of a brown powder.
Melting point: 220xc2x0 C.
1H NMR (CDCl3): 2.91 (s, 3H); 7.54 (d, 1H, J=4.8 Hz); 7.75 (dd, 1H, J=4 and 7.6 Hz); 8.67 (dd, 1H, J=2 and 7.6 Hz); 8.91 (d, 1H, J=4.8 Hz); 9.12 (dd, 1H, J=2 and 4 Hz).
13C NMR (CDCl3): 22.75; 127.93; 128.04; 129.32; 131.50; 135.50; 148.73; 149.26; 152.11; 153.68; 155.47; 181.46; 182.87.
IR (CHCl3): 1689 cmxe2x88x921.
Intermediate (II-1b): 4-methylpyrido[3,2-g]quinoline-5,10-dione
160 mg (Yield: 23%) in the form of a brown powder.
Melting point: 270xc2x0 C.
1H NMR (CDCl3): 2.94 (s, 3H); 7.52 (d, 1H, J=4.8 Hz); 7.76 (dd, 1H, J=4.8 and 8.4 Hz); 8.59 (dd, 1H, J=2 and 8.4 Hz); 8.92 (d, 1H, J=xe2x88x924.8 Hz); 9.11 (dd, 1H, J=2 and 4.8 Hz).
13C NMR (CDCl3): 22.81; 128.30; 128.39; 130.84; 131.55; 135.52; 147.90; 149.95; 151.74; 153.94; 155.35; 180.42; 184.02.
IR (CHCl3) 1672; 1700.
B-2: Synthesis of 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-2b) and of 6-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-2b)
A mixture of 0.5 g (2.8 mmol) of 4-methoxyquinoline-5,8-dione, 0.32 g (2.87 mmol) of crotonaldehyde dimethylhydrazone and 0.4 ml (4.23 mmol) of acetic anhydride in 8 ml of CHCl3 are brought to reflux for 1 hour. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (98/2 CH2Cl2/MeOH) to give 0.48 g of a mixture of the two isomers I-2a and II-2a in the form of a purple powder. This powder and 2.3 g (26.45 mmol) of MnO2 are suspended in 26 ml of CHCl3 and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH2Cl2/MeOH) to give:
Intermediate I-2b: 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione
57 mg (Yield: 8%) in the form of a red powder.
1H NMR (CDCl3): 2.84 (s, 3H); 4.06 (s, 3H); 7.18 (d, 1H, J=6 Hz); 7.46 (d, 1H, J=4.4 Hz); 8.87 (d, 1H, J=6 Hz); 8.87 (d, 1H, J=4.4 Hz).
Intermediate II-2b: 6-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
293 mg (Yield: 40%) in the form of an orange powder.
1H NMR (CDCl3): 2.80 (s, 3H); 4.05 (s, 3H); 7.2 (d, 1H, J=6 Hz); 7.48 (d, 1H, J=4.8 Hz); 8.85 (d, 1H, J=6 Hz); 8.88 (d, 1H, J=4.8 Hz).
13C NMR (CDCl3): 21.75; 43.41; 112.74; 119.72; 130.93; 131.04; 148.32; 149.22; 150.26; 151.60; 152.80; 155.11; 181.44; 184.53.
IR (CHCl3): 1675; 1700 cmxe2x88x921.
B-3: Synthesis of 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-5b) and of 6-nitro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-5b)
A mixture of 0.8 g (3.92 mmol) of 4-nitroquinoline-5,8-dione, 0.65 g (5.8 mmol) of crotonaldehyde dimethylhydrazone and 0.55 ml (5.8 mmol) of acetic anhydride in 10.5 ml of CHCl3 are treated in an ultrasonic bath for 30 min. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (98/2 CH2Cl2/MeOH) to give 0.7 g of a mixture of the two isomers I-5a and II-5a in the form of a purple powder. This powder and 2.9 g (33.4 mmol) of MnO2 are suspended in 29 ml of CHCl3 and the mixture is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (98/2 CH2Cl2/MeOH) to give:
Intermediate I-5b: 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione
110 mg (Yield: 11%) in the powder form.
1H NMR (CDCl3): 2.98 (s, 3H); 7.19 (d, 1H, J=5.6 Hz); 7.54 (d, 1H, J=4.8 Hz); 8.79 (d, 1H, J=5.6 Hz); 8.94 (d, 1H, J=4.8 Hz).
IR (CHCl3): 1703 cmxe2x88x921.
Intermediate II-5b: 6-nitro-4-methylpyrido[3,2-g]quinoline-5,10-dione
165 mg (Yield: 16%) in the form of a yellow-brown powder.
1H NMR (CDCl3): 2.85 (s, 3H); 7.6 (d, 1H, J=4.8 Hz); 7.74 (d, 1H, J=4.8 Hz); 8.99 (d, 1H, J=4.8 Hz); 9.33 (d, 1H, J=4.8 Hz).
B-4: Synthesis of 9-dimethylamino-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-3b) and of 6-dimethylamino-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-3b)
150 mg (0.558 mmol) of nitrated tricycle I-5a or II-5a and 0.4 ml (1.95 mmol) of N,N-dimethylformamide diethyl acetal are dissolved in 2.1 ml of DMF and the reaction mixture is heated at 130xc2x0 C. for 1 hour. After evaporating the solvent with a vacuum pump, 140 mg of intermediate compound II-3a or II-3b are obtained, which material will be used as is in the following stage:
Intermediate II-3b: 6-dimethylamino-4-methylpyrido[3,2-g]quinoline-5,10-dione
Yield: 94%.
1H NMR (CDCl3): 2.77 (s, 3H); 3.05 (s, 6H); 6.89 (d, 1H, J=6 Hz); 7.39 (d, 1H, J=4.8 Hz); 8.42 (d, 1H, J=6 Hz); 8.74 (d, 1H, J=4.8 Hz).
B-5: Synthesis of 9-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione (Intermediate I-7b) and of 6-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione (Intermediate II-7b)
A mixture of 0.6 g (3.1 mmol) of 4-chloroquinoline-5,8-dione, 0.75 g (3.1 mmol) of dimethylhydrazone 4 and 0.45 ml (4.76 mmol) of acetic anhydride in 8.5 ml of CHCl3 are treated in an ultrasonic bath for 30 min. After evaporating the solvent on a rotary evaporator, 2.7 g (31.1 mmol) of MnO2 and 22 ml of CHCl3 are added to the reaction mixture, which is brought to reflux for 2 hours. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (99/1 CH2Cl2/MeOH) to give:
Intermediate I-7b: 9-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione:
70 mg (Yield: 6%) in the form of a brown powder.
1H NMR (CDCl3): 1.35 (s, 9H); 3.45-3.52 (m, 4H); 4.86 (broad s, 1H); 7.56 (d, 1H, J=4.0 Hz); 7.74 (d, 1H, J=5.2 Hz); 8.90 (d, 1H, J=5.2 Hz); 8.94 (d, 1H, J=4 Hz).
13C NMR (CDCl3): 28.37; 35.32; 40.30; 79.47; 126.84; 128.04; 130.88; 131.17; 145.78; 150.34; 150.98; 152.29; 154.05; 154.36; 155.88; 179.76; 182.32.
IR (CHCl3): 1695 cmxe2x88x921.
Intermediate II-7b: 6-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione
200 mg (Yield: 17%) in the form of a brown powder.
13C NMR (CDCl3): 28.24; 34.96; 40.33; 79.47; 128.46; 130.15; 131.06; 131.59; 145.20; 148.76; 149.71; 151.74; 153.88; 153.92; 155.84; 179.76; 183.20.
IR (CHCl3): 1705 cmxe2x88x921.
B-6: Synthesis of 3-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-8b) and of 3-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-8b)
A mixture of 1 g (6.28 mmol) of quinoline-5,8-dione and 1.78 g (12.57 mmol) of 2-methoxy-2-butenal dimethylhydrazone in 25 ml of CHCl3 are stirred at ambient temperature for 5 hours. After evaporating the solvent on a rotary evaporator, the reaction mixture is filtered through silica (95/5 CH2Cl2/MeOH) to give 1.55 g of a mixture of the two isomers I-8a and II-8a in the form of a purple powder. This powder and 1 g (11.5 mmol) of MnO2 are suspended in 30 ml of CHCl3 and the mixture is stirred at ambient temperature for 1 hour. After filtering through celite, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a silica column (99/1 CH2Cl2/MeOH) to give:
Intermediate I-8b: 3-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione
110 mg (Yield: 7%) in the form of a brown powder.
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.79 (s, 3H); 4.11 (s, 3H); 7.72 (dd, 1H, J=4.8 and 8,1 Hz); 8.66 (s, 1H); 8.67 (dd, 1H, J=8.1 and 1.9 Hz); 9.10 (dd, 1H, J=4.8 and 1.9 Hz).
13C NMR (CDCl3): 13.03; 56.87; 127.88; 129.50; 129.95; 135.50; 136.64; 139.26; 142.56; 149.33; 155.11; 157.24; 180.63; 183.56.
IR (CHCl3): 1684 cmxe2x88x921.
Intermediate II-8b: 3-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
190 mg (Yield: 12%) in the form of a brown powder.
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.77 (s, 3H); 4.12 (s, 3H); 7.74 (dd, 1H, J=4.6 and 8.0 Hz); 8.60 (dd, 1H, J=8.0 and 1.6 Hz); 8.68 (s, 1H); 9.12 (dd, 1H, J=4.6 and 1.6 Hz).
13C NMR (CDCl3): 12.98; 56.93; 127.99; 129.06; 131.27; 135.53; 136.84; 138.81; 143.27; 148.16; 155.20; 157.16; 179.69; 184.59.
IR (CHCl3): 1670; 1692 cmxe2x88x921.
B-7: Synthesis of 3,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-9b) and of 3,6-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-9b)
A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform is added dropwise to a solution of 4-methoxyquinolinedione (1.33 g, 7 mmol) in 30 ml of chloroform. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light for 5 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl3, then 98/2 CHCl3/MeOH, then 95/5 CHCl3/MeOH) to produce a first fraction F1 comprising the nonaromatic product and a second fraction F2 comprising the expected product. 1 g of MnO2 is added to the fraction F1 and 30 ml of chloroform. The mixture is left stirring for 90 min. After filtering through celite and washing the precipitate with CHCl3 and then with MeOH, the filtrate is concentrated on a rotary evaporator to produce a fraction F1xe2x80x2. The fractions F1xe2x80x2 and F2 are combined and then purified by flash chromatography through silica (CHCl3 and then 97/3 CHCl3/MeOH) to give the two expected compounds I-9a and II-9b in the form of a brown powder.
Intermediate (II-9b): 3,6-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
Yield: 11% (210 mg).
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.68 (s, 3H) 4.09 (s, 3H); 4.10 (s, 3H); 7.18 (d, 1H, J=5.5 Hz); 8.60 (s, 1H); 8.88 (d, 1H, J=5.5 Hz).
13C NMR (CDCl3): 12.85; 56.81; 56.84; 111.14; 121.32; 130.95; 136,43; 137.79; 141.95; 150.31; 155.44; 157.33; 165.97; 180.13; 184.24.
IR (CHCl3): 1678, 1692 cmxe2x88x921.
B-8xe2x80x94Synthesis of 3-methoxy-4-methyl-9-chloropyrido[2,3-g]quinoline-5,10-dione (Intermediate I-10b) and of 3-methoxy-4-methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione (Intermediate II-10b)
A solution of 2-methoxy-2-butenal dimethylhydrazone (1 g, 7.1 mmol) in 15 ml of chloroform is added dropwise to a solution of 4-chloroquinolinedione (1.37 g, 7.1 mmol) in 30 ml of chloroform. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 5 h 30. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl3, then 98/2 CHCl3/MeOH) to produce a first fraction F1 comprising the nonaromatic product. 1 g of MnO2 is added to this fraction F1 and 30 ml of chloroform. The mixture is left stirring at ambient temperature for 60 min. After filtering through celite and washing the precipitate with CHCl3 and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (97/3 [lacuna]) to give the compounds I-10b and II-10b in the form of a yellow powder.
Intermediate II-10b: 3-methoxy-4-methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione
Yield: 5% (100 mg).
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.68 (s, 3H); 4.11 (s, 3H); 7.71 (d, 1H, J=5.2 Hz); 8.64 (s, 1H); 8.90 (d, 1H, J=5.2 Hz).
13C NMR (CDCl3): 12.96; 56.97; 128.92; 130.72; 130.98; 136.95; 138.12; 141.93; 145.06; 150.21; 153.85; 157.55; 179.31; 183.67.
IR (CHCl3): 1696; 1684 cmxe2x88x921.
B-9: Synthesis of 3-methoxy-4-methyl-9-dimethylaminopyrido[2,3-g]quinoline-5,10-dione (Intermediate I-11b) and of 3-methoxy-4-methyl-6-dimethylaminopyrido[3,2-g]quinoline-5,1-dione (Intermediate II-11b)
A solution of I-10b or of II-10b (90 mg, 0.31 mmol), of dimethylammonium chloride (127 mg, 1.56 mmol) and of NaOH (63 mg, 1.56 mmol) in a THF/H2O (4 ml/2 ml) mixture is brought to reflux for 1 hour. After evaporating the solvent on a rotary evaporator, the crude product obtained is taken up in a 95/5 CH2Cl2/MeOH mixture (50 ml). The organic phase is recovered and then dried over MgSO4. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (95/5 CH2Cl2/MeOH) to give the expected compounds I-11b or II-11b in the form of a yellow powder.
Intermediate II-11b: 3-methoxy-4-methyl-6-dimethylaminopyrido[3,2-glguinoline-5,10-dione
Yield: 87% (80 mg).
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.64 (s, 3H); 3.06 (s, 6H); 4.08 (s, 3H); 6.95 (d, 1H, J=5.9 Hz); 8.53 (d, 1H, J=5.9 Hz); 8.56 (s, 1H).
13C NMR (CDCl3): 12.62; 43.40; 56.80; 112.39; 120.50; 132.23; 135.90; 136.08; 141.86; 150.53; 151.70; 155.04; 157.19; 180.67; 185.45.
IR (CHCl3): 1693; 1654 cmxe2x88x921.
B-10: Synthesis of 3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-12b) and of 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-12b)
1xe2x80x94Synthesis of 2-methoxyquinoline-5,8-dione
A suspension of 5,8-dioxocarbostyryl (3.1 g, 17.7 mmol), of silver carbonate (10.2 g, 37 mmol) and of methyl iodide (31 ml, 498 mmol) in 1.2 l of CHCl3 is stirred in the dark at ambient temperature for 90 hours. The precipitate is removed by filtration and the filtrate is concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (CHCl3) to give the expected quinone in the form of a yellow solid (2.2 g).
Yield: 66%).
Melting point: 196xc2x0 C.
1H NMR (CDCl3): 4.14 (s, 3H); 6.95 (d, 1H, J=10.3 Hz); 7.02 (d, 1H, J=10.3 Hz); 7.06 (d, 1H, J=8.8 Hz); 8.25 (d, 1H, J=8.8 Hz).
13C NMR (CDCl3): 54.70; 116.68; 124.32; 136.83; 137.54; 138.21; 146.58; 167.14; 183.48; 184.31.
2xe2x80x94Synthesis of 3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-12b) and of 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-12b)
A solution of 2-methoxy-2-butanal dimethylhydrazone (0.75 g, 5.3 mmol) in 10 ml of THF is added dropwise to a solution of methoxyquinolinedione (1.0 g, 5.3 mmol) in 60 ml of THF. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 40 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is dissolved in 80 ml of CHCl3 and 85% MnO2 (5.4 g, 53 mmol) is added. The reaction mixture is kept stirred for 2 hours and is then filtered through celite. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (CHCl3) to give the compounds I-12b and II-12b in the form of a brown powder.
Intermediate II-12b: 3,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
Yield: 8% (120 mg).
Melting point:  greater than 260xc2x0 C.
1H NMR (CDCl3): 2.74 (s, 3H); 4.09 (s, 3H); 4.20 (s, 3H); 7.09 (d, 1H, J=8.4 Hz); 8.41 (d, 1H, J=8.4 Hz); 8.63 (s, 1H).
13C NMR (CDCl3):
IR (CHCl3): 1667, 1693 cmxe2x88x921.
B-11: Synthesis of 8-ethoxycarbonyl-8-(2xe2x80x2-N-BOC-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (Intermediate I-13b) and of 7-ethylcarbonyl-6(2xe2x80x2-N-BOC-aminoethyl)pyrido[3,2-g]quinoline 5,10-dione (Intermediate II-13b)
A solution of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (1.1 g, 4.56 mmol) in 15 ml of acetonitrile is added dropwise to a solution of 3-ethylquinolinecarboxylate-5,8-dione (1.05 g, 4.54 mmol) and of acetic anhydride (4.6 ml) in 75 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 24 hours. After evaporating the solvent on a rotary evaporator, 5 g of MnO2 and 150 ml of chloroform are added to the crude product obtained. The mixture is left stirring at ambient temperature for 1 h 30. After filtering through celite and washing the precipitate with CHCl3 and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified, first by filtration through silica (99/1 and then 97/3 CH2Cl2/MeOH) and then by flash chromatography through silica (99/1), to give the compounds I-13b and II-13b in the form of a brown powder.
Intermediate II-13b: 7-ethoxycarbonyl-6-(2xe2x80x2-N-BOC-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione
Yield: 3% (60 mg).
Melting point: 170xc2x0 C.
1H NMR (CDCl3): 1.36 (s, 9H); 1.47 (t, 3H, J=7.4 Hz); 3.52 (m, 4H); 4.51 (q, 2H, J=7.4 Hz); 4.78 (broad 9, 1H); 7.57 (d, 1H, J=5.2 Hz); 8.99 (d, 1H, J=5.2 Hz); 9.17 (d, 1H, J=2.2 Hz); 9.64 (d, 1H, J=2.2 Hz).
13C NMR (CDCl3): 14.33; 28.40; 35.74; 40.22; 62.62; 79.63; 128.65; 130.33; 130.49; 131.83; 137.30; 149.60; 150.23; 152.72; 154.23; 155.72; 155.98; 163.52; 179.69; 183.38.
IR (CHCl3): 3457; 1726; 1705; 1677 cmxe2x88x921.
B-12: Synthesis of 7-hydroxy-4-(2xe2x80x2-N-Boc-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (Intermediate I-14b) and of 8-hydroxy-4-(2xe2x80x2-N-Boc-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione (Intermediate II-14b)
A solution of N-BOC-5-amino-2-penten-1-al dimethylhydrazone (1.49 g, 6.15 mmol) in 30 ml of acetonitrile is added dropwise to a solution of 5,8-dioxocarbostyril (0.98 g, 5.59 mmol) and of acetic anhydride (5.8 ml) in 100 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 16 hours. After evaporating the solvent on a rotary evaporator, 7 g (80.5 mmol) of MnO2 and 180 ml of chloroform are added to the crude product obtained. The mixture is left stirring at ambient temperature for 1 h 30. After filtering through celite and washing the precipitate with CHCl3 and with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (98/2 and then 95/5 CH2Cl2/MeOH) to give the compound I-14b and II-14b in the form of a brown powder.
Intermediate II-14b: 8-hydroxy-4-(2xe2x80x2-N-Boc-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione
Yield: 12% (230 mg).
Melting point: 252xc2x0 C.
1H NMR (CDCl3): 1.56 (s, 9H); 3.49 (m, 4H); 4.73 (broad s, 1H); 6.94 (d, 1H, J=9.6 Hz); 7.54 (d, 1H, J=4.8 Hz); 8.10 (d, 1H, J=9.6 Hz); 8.89 (d, 1H, J=4.8 Hz); 9.66 (broad s, 1H).
13C NMR (CDCl3): 28.29; 35.53; 40.24; 117.01; 127.87; 128.62; 132.29; 136.18; 138.04; 148.25; 152.26; 153.33; 155.86; 176.36; 181.35.
IR (CHCl3): 3457; 3340; 1693; 1663 cmxe2x88x921.
B-13: Synthesis of 7-hydroxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-15b) and of 8-hydroxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-15b)
A solution of 2-butenal dimethylhydrazone (0.703 g, 6.28 mmol) in 20 ml of acetonitrile is added dropwise to a solution of 5,8-dioxocarbostyril (1 g, 5.71 mmol) and of acetic anhydride (6.2 ml) in 220 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 16 hours and is then heated at reflux for 6 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is purified by filtration through silica (CH2Cl2 and then 98/2 CH2Cl2/MeOH) to produce a first fraction comprising the nonaromatic product and the expected product. 3 g of MnO2 and 75 ml of chloroform are added to the mixture, which is left stirring at ambient temperature overnight. After filtering through celite and washing the precipitate with CHCl3 and then with MeOH, the mixture is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (99/1) to give the expected compounds I-15b and II-15b in the form of a beige powder.
Intermediate II-15b: 8-hydroxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
Yield: 12%.
Melting point:  greater than 260xc2x0 C.
1H NMR (d6-DMSO): 2.79 (s, 3H); 6.82 (d, 1H, J=9.5 Hz); 7.73 (d, 1H, J=5.2 Hz); 8.05 (d, 1H, J=9.5 Hz); 8.85 (d, 1H, J=5.2 Hz); 12.27 (broad s, 1H).
13C NMR (d6-DMSO): 21.92; 114.30; 122.66; 127.30; 131.52; 135.94; 148.60; 149.80; 152.48 (2C); 176.41; 182.13 (2C).
IR (CHCl3): 1684; 1664 cmxe2x88x921.
B-14: Synthesis of 7-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-16b) and of 8-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-16b)
A mixture of compound I-15b or II-15b (70 mg, 0.29 mmol), of methyl iodide (1 ml, 15.9 mmol) and of Ag2CO2 (170 mg, 0.62 mmol) in 100 ml of CHCl3 is stirred at ambient temperature and with the exclusion of light for 14 hours and is then heated at 56xc2x0 C. for 5 hours. After concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography through silica (99.5/0.5 CH2Cl2/MeOH) to give the expected compounds I-16b or II-16b in the form of a beige-brown powder.
Intermediate II-16b: 8-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione.
Yield: 41% (30 mg).
Melting point: 128xc2x0 C.
1H NMR (CDCl3): xe2x88x924.14 (s, 3H); 7.07 (d, 1H, J=8.8 Hz); 7.44 (d, 1H, J=4.8 Hz); 8.37 (d, 1H, J=8.8 Hz); 8.85 (d, 1H, J=4.8 Hz).
13C NMR (CDCl3): 54.92; 117.58; 126.24; 128.09; 131.30; 137.73; 147.31; 150.00; 151.34; 153.38; 167.39; 180.44; 183.70.
IR (CHCl3): 1765; 1698; 1667; 1603 cmxe2x88x921.
B-15: Synthesis of 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-17b) and of 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-17b)
1. Synthesis of 2,4-dichloroquinoline-5,8-dione
Cerium ammonium nitrate (CAN 21.4 g, 39.03 mmol) is added portionwise to a solution of 2,4-dichloro-5,8-dimethoxyquinoline (2.85 g, 11.04 mmol) in a CH3CN/H2O mixture (150 ml/75 ml). The reaction mixture is stirred at ambient temperature for 40 min. The acetonitrile is subsequently evaporated and 50 ml of water and 200 ml of a saturated NaHCO3 solution are added. The aqueous phase is extracted with CH2Cl2 (5 times 200 ml). After drying over MgSO4, the solvent is evaporated on a rotary evaporator to give the expected compound in the form of a brown powder (1.9 g).
Yield: 75%.
Melting point: 161xc2x0 C.
1H NMR (CDCl3): 7.03 (d, 1H, J=10.6 Hz); 7.11 (d, 1H, J=10.6 Hz); 7.74 (s, 1H).
13C NMR (CDCl3): 124.43; 131.10; 136.91; 139.52; 146.69; 148.96; 156.16; 180.53; 182.01.
IR (CHCl3): 1687; 1676 cmxe2x88x921.
2. Synthesis of 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate I-17b) and of 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-17b)
A solution of 2-butenal dimethylhydazone (0.325 g, 2.89 mmol) in 20 ml of acetonitrile is added dropwise to a solution of 2,4-dichloroquinoline-5,8-dione (0.6 g, 2.63 mmol) and of acetic anhydride (5 ml) in 100 ml of acetonitrile. The reaction mixture is kept stirred at ambient temperature, under nitrogen and with the exclusion of light, for 20 hours. After evaporating the solvent on a rotary evaporator, the crude product obtained is taken up in 140 ml of CHCl3. 3.65 g of MnO2 are subsequently added and then the mixture is left stirring at ambient temperature for 56 hours. After filtering through celite and washing the precipitate with CHCl3 and then with MeOH, the solution is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography through silica (CH2Cl2) to give the expected compounds I-17b and II-17b in the form of a brown powder.
Intermediate II-17b: 6,8-dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione
Yield: 41% (314 mg).
Melting point: 177xc2x0 C.
1H NMR (CDCl3): 2.87 (s, 3); 7.56 (d, 1H, J=4.8 Hz); 7.79 (s, 1H); 8.93 (d, 1H, J=4.8 Hz).
13C NMR (CDCl3): 22.41; 125.44; 127.84; 131.13; 131.30; 147.44; 149.81; 150.62; 151.90; 154.30; 156.58; 179.12; 180.66.
IR (CHCl3): 1706; 1683 cmxe2x88x921.
B-16xe2x80x94Synthesis of 7,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (Intermediate 1-18b) and of 6,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-18b)
A mixture of compound I-17b or of compound II-17b (80 mg, 0.27 mmol) and of sodium methoxide (300 mg of Na in 40 ml of methanol, 13.04 mmol) in 40 ml of methanol is brought to ref lux for 17 hours. The reaction mixture is concentrated to dryness and then 50 ml of water are added. After neutralizing with 25% HCl, the solution is extracted with CH2Cl2 (3 times 50 ml). After drying over MgSO4 and evaporating the solvent on a rotary evaporator, the expected compounds I-18b or II-18b [lacuna] quantitatively.
Intermediate II-18b: 6,8-dimethoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione
Melting point: 219xc2x0 C.
1H NNR (CDCl3): 2.88 (s, 1H); 4.03 (s, 3H); 4.07 (s, 3H); 6.53 (s, 1H); 7.45 (d, 1H, J=4.8 Hz); 8.83 (d, 1H, J=4.8 Hz).
13C NMR (CDCl3): 22.64; 54.73; 56.80; 97.79; 117.61; 129.55; 131.46; 148.67; 149.41; 150.73; 152.96; 167.95; 168.00; 180.91; 183.41.
IR (CHCl3): 1701; 1668 cmxe2x88x921.